A range of drug delivery systems for local, controlled and/or targeted delivery therapy has been developed in the past. Many are based on bioresorbable (or biodegradable) polymers, bioresorbable ceramics and/or hydrogel(s) as carriers for the therapeutically active substance. Commonly used biodegradable polymers are polylactic acids and polylactic-co-glycolide-acids. Various calcium-salt based ceramics, e.g. calcium phosphate or calcium sulphate systems, or hydroxylapatite, have been described in the form of beads, granules, scaffolds or moldable pastes, to carry and release drugs in both active and inactive form, e.g. hormones, antibiotics, antiviral, anticancer, analgesic, anticoagulant and bone growth factors to surrounding tissues. These ceramics are often referred to as hydratable or hydrating ceramics due to their ability to react chemically with water to form hydrates. See e.g. Royer U.S. Pat. No. 6,391,336, U.S. Pat. No. 6,630,486, US 2003/0170307.
When bioresorbable (or biodegradable) and hydratable ceramic carriers are used, the release mechanisms rely on the inherent properties of the hydratable ceramic materials after solidification through hydration. For example, calcium sulphate in the form of its hemi-hydrate rapidly binds additional water and forms the calcium-sulphate di-hydrate. When a mixture of ceramic powder and active drug is exposed to water and hydrates, the active drug or prodrug is bound into a matrix/carrier of the hydrated material. Due to a combination of factors such as the limited amount of water possible to bind in the hydration reactions, limiting the possible amount of hydrate phases being formed to fill the gaps between powder grains, and the necessity for at least some water transport for the hydration to proceed, some degree of porosity remains after hydration. The porosity formed as a result of normal hydration is often referred to as the residual micro-porosity. After a normal hydration of calcium sulphate hemi-hydrate the micro-porosity constitutes about 30-50 vol. %. In an in vivo situation, the active drug or prodrug is released from the carrier, entering the surroundings, by mechanisms involving e.g. diffusion through the pore system and/or erosion of the carrier material.
Ceramic substances as e.g. calcium sulphate have been suggested as implant materials for controlled release of active substances (see e.g. Royer U.S. Pat. No. 6,391,336, U.S. Pat. No. 6,630,486, US 2003/0170307). In order to obtain a slower and controlled release of the active substance(s) from the ceramics, Royer uses a complexing agent that is a polymeric substance that forms a complex with the active substance, whereby a slower drug release may be obtained.
The bioresorbable ceramics have many favorable properties for pharmaceutical formulations in controlled release applications as compared to polymers, such as biocompatibility and biodegradability. In general, the bioresorbable ceramics are non-toxic and are based on molecules which normally occurring in the living tissues of mammals. Calcium sulphate is particularly attractive since it is a resorbable and biocompatible material, i.e. it disappears over time.
However, the release rate of therapeutic substances from ceramic carriers has turned out to be difficult to control. For both calcium phosphate and calcium sulphate based ceramic systems, the release rate is too high for a long-term drug delivery system. Furthermore, in some cases formulations are desired, which offer a combination of an immediate and/or rapid boost-like therapeutic dose in combination with a slower and controlled release dosing over a prolonged period of time.
The PCT-application WO 05/039537 discloses a pharmaceutical composition comprising a bioresorbable hydratable ceramic, sorbed aqueous medium, and an active substance. In the described composition the release rate is controlled by sealing the porosity.
This invention offers a technique to reduce and control the drug release rate of a bioresorbable and hydratable ceramic when used as a carrier for therapeutic agents. With the invention also combinations of more rapid release and slower release characteristics in the same pharmaceutical formulation can be achieved.